Immunogenetic markers associated with a naturally acquired humoral immune response against an N-terminal antigen of Plasmodium vivax merozoite surface protein 1 (PvMSP-1)

São Paulo State University. Department of Biology. São José do Rio Preto, SP, Brazil / São José do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. São José do Rio Preto, SP, Brazil.São José do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. São José do Rio Preto, SP, Brazil.São José do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. São José do Rio Preto, SP, Brazil / São Paulo State University. Department of Biology. São José do Rio Preto, SP, Brazil.Federal University of Sergipe. Department of Biology. São Cristóvão, SE, Brazil.Oswaldo Cruz Foundation. Leônidas and Maria Deane Institute. Manaus, AM, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Pesquisa Básica de Malária. Belém, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Pesquisa Básica de Malária. Belém, PA, Brasil.Oswaldo Cruz Foundation. Leônidas and Maria Deane Institute. Manaus, AM, Brazil.São Paulo State University. Department of Biology. São José do Rio Preto, SP, Brazil / São José do Rio Preto Medical School. Department of Skin. Infectious and Parasitic Diseases. São José do Rio Preto, SP, Brazil / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Pesquisa Básica de Malária. Belém, PA, Brasil.Background: Humoral immune responses against proteins of asexual blood-stage malaria parasites have been associated with clinical immunity. However, variations in the antibody-driven responses may be associated with a genetic component of the human host. The objective of the present study was to evaluate the influence of co-stimulatory molecule gene polymorphisms of the immune system on the magnitude of the humoral immune response against a Plasmodium vivax vaccine candidate antigen. Methods: Polymorphisms in the CD28, CTLA4, ICOS, CD40, CD86 and BLYS genes of 178 subjects infected with P. vivax in an endemic area of the Brazilian Amazon were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The levels of IgM, total IgG and IgG subclasses specific for ICB2-5, i.e., the N-terminal portion of P. vivax merozoite surface protein 1 (PvMSP-1), were determined by enzyme-linked immuno assay. The associations between the polymorphisms and the antibody response were assessed by means of logistic regression models. Results: After correcting for multiple testing, the IgG1 levels were significantly higher in individuals recessive for the single nucleotide polymorphism rs3116496 in CD28 (p = 0.00004). Furthermore, the interaction between CD28 rs35593994 and BLYS rs9514828 had an influence on the IgM levels (p = 0.0009). Conclusions: The results of the present study support the hypothesis that polymorphisms in the genes of co-stimulatory components of the immune system can contribute to a natural antibody-driven response against P. vivax antigens

No evidence for association of the CD40, CD40L and BLYS polymorphisms, B-cell co-stimulatory molecules, with Brazilian endemic Plasmodium vivax malaria

Background: Plasmodium vivax is the most prevalent malaria species in Brazil. The parasite-host coevolutionary process can be viewed as an 'arms race', in which adaptive genetic changes in one are eventually matched by alterations in the other. Methods: Following the candidate gene approach we analyzed the CD40, CD40L and BLYS genes that participate in B-cell co-stimulation, for associations with P. vivax malaria. The study sample included 97 patients and 103 controls. We extracted DNA using the extraction and purification commercial kit and identified the following SNPs: 21C.T in the CD40 gene, 2726T.C in the CD40L gene and the 2871C.T in the BLyS gene using PCR-RFLP. We analyzed the genotype and allele frequencies by direct counting. We also compared the observed with the expected genotype frequencies using the Hardy-Weinberg equilibrium. Results: The allele and genotype frequencies for these SNPs did not differ statistically between patient and control groups. Gene-gene interactions were not observed between the CD40 and BLYS and between the CD40L and BLYS genes. Overall, the genes were in Hardy-Weinberg equilibrium. Significant differences were not observed among the frequencies of antibody responses against P. vivax sporozoite and erythrocytic antigens and the CD40 and BLYS genotypes. Conclusions: The results of this study show that, although the investigated CD40, CD40L and BLYS alleles differ functionally, this variation does not alter the functionality of the molecules in a way that would interfere in susceptibility to the disease. The variants of these genes may influence the clinical course rather than simply increase or decrease susceptibility. © Royal Society of Tropical Medicine and Hygiene 2013. All rights reserved

Polymorphisms in B Cell Co-Stimulatory Genes Are Associated with IgG Antibody Responses against Blood–Stage Proteins of <i>Plasmodium vivax</i>

<div><p>The development of an effective immune response can help decrease mortality from malaria and its clinical symptoms. However, this mechanism is complex and has significant inter-individual variation, most likely owing to the genetic contribution of the human host. Therefore, this study aimed to investigate the influence of polymorphisms in genes involved in the costimulation of B-lymphocytes in the naturally acquired humoral immune response against proteins of the asexual stage of <i>Plasmodium vivax</i>. A total of 319 individuals living in an area of malaria transmission in the Brazilian Amazon were genotyped for four SNPs in the genes <i>CD40</i>, <i>CD40L</i>, <i>BLYS</i> and <i>CD86</i>. In addition, IgG antibodies against <i>P</i>. <i>vivax</i> apical membrane antigen 1 (PvAMA–1), Duffy binding protein (PvDBP) and merozoite surface protein 1 (PvMSP–1₁₉) were detected by ELISA. The SNP <i>BLYS</i> –871C>T was associated with the frequency of IgG responders to PvAMA–1 and PvMSP–1₁₉. The SNP <i>CD40</i> –1C>T was associated with the IgG response against PvDBP, whereas IgG antibody titers against PvMSP–1₁₉ were influenced by the polymorphism <i>CD86</i> +1057G>A. These data may help to elucidate the immunological aspects of vivax malaria and consequently assist in the design of malaria vaccines.</p></div

Summary of the epidemiological data and seropositivity of the study population.

<p>Summary of the epidemiological data and seropositivity of the study population.</p

Positive antibody response and carrier frequency of mutant alleles.

<p>Frequency of carriers of mutant alleles of SNPs in genes <i>CD40</i>, <i>BLYS</i>, <i>CD86</i>, and <i>CD40L</i> according to the number of proteins for which subjects were responders. Individuals with antibodies against the three proteins (n = 279) were classified according to their reaction against zero (n = 57), one (n = 55), two (n = 38), or three (n = 129) proteins of blood-stage <i>P</i>. <i>vivax</i>.</p

<i>BLYS</i>, <i>CD40</i>, <i>CD86</i>, and <i>CD40L</i> genotypes in relation to antibody titers against the merozoite proteins.

<p>Antibody titers were expressed as log-transformed reactivity indices (RI). For the SNP in the gene <i>CD40L</i>, men and women harboring the C allele were grouped and compared with individuals who did not possess this allele given that <i>CD40L</i> is located on chromosome X. Multivariate logistic regression analysis found no significant differences in the antibody titers between the different genotypes.</p

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys